Method of making pyrrole derivatives

ABSTRACT

Heterocyclic nitrogen compounds, especially aziridine and pyrrole derivatives, are formed by addition of organic acid chlorides at the carbon double bond of single-unsaturated hydrocarbon chlorinated at the carbon atom adjacent to the double bond, said addition taking place in the presence of a Lewis-acid at low temperatures. The obtained dichloroketone is reacted in a second stage with amines or ammonia to form the heterocyclic compound. At temperatures above 100* C pyrrole derivatives are obtained; below 100* C aziridine derivatives are formed. Heterocyclic nitrogen compounds with various substituents can be prepared from the correspondingly selected base substances.

United States Patent Rosenmund et a1.

[ 1 Aug. 29, 1972 METHOD OF MAKING PYRROLE DERIVATIVES Inventors: PeterRosenmund, Domigheim;

Klaus Grubel, Julich, both of Germany Assignee: Friedrich-Karl Marcus,Geesthacht,

Germany Filed: April 1, 1969 Appl. No.: 812,301

Int. Cl. ..C07d 23/06, C07d 27/26 FieldofSearch ..260/313.l, 296RReferemes Cited UNITED STATES PATENTS 11/1949 Scott ..260/3l3.1

Primary Examiner-Alex Maul Assistant Examiner-Joseph A. NarcavageAtt0rneyBeaman & Beaman [57] ABSTRACT Heterocyclic nitrogen compounds,especially aziridine and pyrrole derivatives, are formed by addition oforganic acid chlorides at the carbon double bond of single-unsaturatedhydrocarbon chlorinated at the carbon atom adjacent to the double bond,said addition taking place in the presence of a Lewis-acid at lowtemperatures. The obtained dichloroketone is reacted in a second stagewith amines or ammonia to form the heterocyclic compound. Attemperatures above 100 C pyrrole derivatives are obtained; below 100 Caziridine derivatives are formed. Heterocyclic nitrogen compounds withvarious substituents can be prepared from the correspondingly selectedbase substances.

11 Claims, No Drawings 1 METHOD OF MAKING PYRROLE DERIVATIVES BACKGROUNDOF THE INVENTION Heterocyclic nitrogen compounds, especially pyrrolederivatives are widely spread in nature. Examples of this are bloodpigment, chlorophyll, many alkaloids and albumen components. Therefore,pyrrole derivatives meet with considerable interest in the drug industryas basic substances for pharmaceutical products and in the chemicalindustry, here above all as starting substances for the production ofpigments.

Although pyrrole was discovered in tar already in 1834 by Otto Runge andobtained in pure form for .the first time in [858 by Andersen and aplurality of pyrrole syntheses have been developed since, it has notbeen possible up to now to obtain heterocyclic nitrogen compounds,especially pyrrole and an'ridine derivatives, in a simple manner withgood yields, in particular pyrrole derivatives with more than twosubstituents. The basic substances were either difiicult to obtain orexpensive, or the yields were low (reference is made in this connectionto the three volume by H. Fischer and H. Orth, which deals in particularwith the pyrrole derivatives and their syntheses).

The object of the invention is a process for the production ofheterocyclic nitrogen derivatives, especially pyrrole and aziridinederivatives, from available basic substances.

SUMMARY OF THE lNVENTION It has now been found that organic acidchlorides, such as acetyl chloride, propinonyl chloride, butyrylchloride, isobutyryl chloride, benzoyl chloride, nicotinic acidchloride, are added largely according to the rule of Markownikow athalogen compounds of singly unsaturated hydrocarbons which carry thehalogen in neighbor position to the double bond, with a Lewis acid suchas A|c,, BF (anhydrous) functioning as a catalyst. In this addition B,'y-dihalogen ketones are formed which, under suitable conditions, formwith ammonia or primary amines heterocyclic nitrogen derivatives, whichare substituted at least in the 2- The process according to theinvention is characterized in that a halogen compound of asingle-unsaturated hydrocarbon of the general formula R1 R1 R (II) isreacted by heating, with an amine of the general forrnula RB'NH! 2wherein R, may be hydrogen, a straight-chain or branched-chain alkylradical, or a aryl radical, thereby forming the correspondingheterocyclic nitrogen compound by splitting ofi hydrogen chloride andeventually water.

The halogen compound of s single-unsaturated hydrocarbon and the acidchloride are charged in a mole ratio of up to l 3. No solvent isnecessary. If the acid chloride is expensive, the components areemployed preferably in a mole ratio of l 1.2. In this case the additionwill be carried out in a solvent not participating in the reaction, suchas dichloromethane or carbon disulfide.

The addition is carried out in the presence of a catalyst effective asan electron acceptor, for instance a Lewis-acid, such as aluminumchloride, boron trifluoride, at temperatures below 10 C. The B,ydichloroketone obtained does not have to be isolated in its pure formprior to the reaction with the amine.

At least twice the quantity of amine calculated on the dichloroketone isused for the ring closing reaction. In order to preclude largely anyinterfering side reaction and to obtain good yields, it isrecommendable, however, to employ between 5 and 10 moles amine per molB, 'y-dichloroketone. When using ammonia or a lower aliphatic amine, thereaction is carried out in the vapor phase, for instance, in anautoclave or a tubular reactor, and the heterocyclic nitrogen derivativeformed in this reaction is removed from the reaction zone by means ofwater vapor distillation orsome other suitable method.

According to this process, thus, the most various pyrrole derivativesmay be formed, wherein the substitutent in the l-position namely R, isdetennined by the selection of the amine; the substituent in the2-position i.e. the R is determined by the selection of the amine; thesubstituent in the 2-position, i.e., the R is determined by theselection of the type of the acid chloride, and the remainingsubstituents are determined by the selection of the single-unsaturatedhalogenated hydrocarbon (the positions 3, 4 and 5 being occupied by R,,R, and R respectively).

When preparing pyrrole derivatives according to the process of thepresent invention, the ring closure reaction is carried out by heatingto a temperature of C for a time longer than 1 hour.

The following reactions represent the steps taking place when practicingthe process in accordance with the invention with acetyl chloride, allylchloride and ammonia for the preparation of Zmethyl-pyrrole If oneselects methallyl chloride, benzoyl chloride and aniline as basicsubstances, the reaction course is as follows:

The following examples are intended to illustrate the process of theinvention still more clearly but not to restrict in any way theinvention.

It is thus possible by the process of the invention to produce pyrrolederivatives carrying not only one or two but up to five substituents,the type of each individual substituent being predetermined by selectionof the basic substances for the analysis. Thus, the production of aplurality of new pyrrole derivatives has been made possible.

The invention relates also to the subsequent processing of these pyrrolederivatives into the pyrrolines and pyrrolidiness by hydration.Particularly the latter are above all of major importance for theproduction of pharmaceutical products, because now it has been madepossible to obtain pyrrolidines with the respectively desiredsubstituents in the desired positions. Pyrrolidines are components ofquite a number of pharmaceutical products, and it is known that thepharmaceutical effect of a substance may be varied in a certain mannerby alteration of the substituents thereof.

The above described method, however, also still may be modified in asimple manner so that aziridine derivatives are obtained. When carryingout the reaction of the B,y-dicl1loroketone at a temperature below l C aring closure reaction takes place with splitting-off only two moleculesof hydrogen-chloride but no water 5 that means that the keto group ismaintained intact and an aziridine derivative of the general formula ii-Q it. (Vl) is formed.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 250 ml 278 g) acetylchloride are charged into a l l three-neck bottle provided with anagitator and a thermometer, and 140 g (1.2 mol) aluminum chloride areslowly introduced at a temperature of l5 C. The amber colored suspensioncontaining the molecule compound then has added thereto drop by drop,after the bottle has been provided with a dropping funnel, 76.5 g (lmol) of allyl chloride as slowly that ihe temperature inside the bottledoes not exceed -l 0 C. As the reaction is strongly exothermic a goodoutside cooling must be provided so that splitting-oi? hydrogen chloridefrom the formed ketone may be prevented even at the end of the reaction.At the beginning, the solution becomes clear but a precipitation mayoccur at the end of the reaction. The mixture has a medium brown to redcolor. After having added the allyl chloride the agitation is stillcontinued for approximately another quarter of an hour; then the batchis poured into 2,500 g ice water under strong agitation so that in theend there will still be a little ice left. The organic components arethen extracted by means of dichloromethane which then is largely suckedoff under vacuum at ambient temperature. The crude product remains as atransparent dark-brown liquid in a quantity of about l40 g (which isapproximately 90 percent of theory) 4,5-dichlor0-2-pentanon calculatedon the allyl chloride charged. About 75 to 80 g of a colorless liquidwith a hardly biting scent are distilled at 0,5 mm Hg between 48 52 Cwhich, as has been proved by gas chromatography, consists of threedifferent substances present in the ratio of l 5 l5. It may be assumedthat the by-product obtained in smaller quantity is a product obtainedby splitting off hydrogen chloride (acetyl allyl chloride) while thesecond by-product obtained in greater quantity is3-chloromethyl-4-chlorobutanone which is not capable to be reacted topyrroles. The desired compound 4,5-dichloro-2-pentanone is obtained in aquantity of 72 percent of the calculated value. The crude product may bekept for a 65 rcelatively long period of time at a temperature of l 5 97g of the non-distilled crude product obtained above (which correspondsto one half moi 4,5- dichIoro-Z-pentanone) are dissolved in about tentimes the quantity of methanol and are reacted with 5 to mole of aprimary amine or ammonia at 200 C in an autoclave for 2 to 4 hours. Thereaction product may be directly subjected to a water vapordistillation; but it is recommendable to draw off the solvent as well asa part of the excess amine before through a column in a order to avoidunnecessary solvent losses. After processing the distillate of the watervapor distillation by separation of the pyrrole derivative from theaqueous phase in the usual manner and drying, 28 g of 2- methylpyrrolehaving a boiling point of 148 C were obtained when using ammonia whichmeans 70 percent of the calculated value related to the quantity of 4,5-dichloro-Z-pentanone, which was used as a starting substance.

EXAMPLE 2 The process was carried out as in Example 1 with the exceptionthat ethyl amine was employed instead of ammonia. In this process,l-ethyl-2-methyl-pyrrole having a boiling point of 155 159 C wasobtained in a yield of 22.5 g, which is 62 percent of the theory.

EXAMPLE 3 The operation was carried out as in Example 1 but with butyricacid chloride used instead of the acetyl chloride. In this operation the6,7-dichloro-4-eptanone (-83 90 C at 0.5 mm hg) was obtained as anintermediate product likewise not in a pure form, and was reacted withammonia into 2-propylpyrrole (boiling point 0.9 hg: 44 45 C). The yieldwas 35 g corresponding to 69 percent.

With the addition of benzoyl chloride to methallyl chloride a mixture ofreaction products was obtained which shows a boiling interval of 130 180C at 200 mm Hg. This crude product was boiled under reflux withapproximately 10 times the theoretic molar quantity of aniline for up tol4 hours. That portion of the reaction product which is soluble inchloroform showed a variety of substances in the thin-layerchromatography analysis on silica gel with benzene as eluent, thatsubstance of which having the highest RF- value showing a distinctcharacteristic cinnamic aldehyde reaction. According to an estimation ofthe quantities of the individual substances, the yield of the ringclosure reaction should lie between 50 and 65 percent.

EXAMPLE 4:

Acetylchloride was added to allyl chloride as is described in example Iin the presence of AlCl The 4,5-dichloro-2-pentanone-2 was subsequentlyheated with ammonia at temperatures below 100 C. One obtainedZ-acetonyl-aziridine of the formula H: N H

2-acetonyi-azlrldine with a boiling point of 75 77 C, and a yield of 28g, i.e. 60 percent of the theory.

The aziridine derivatives obtained in accordance with the invention arelikewise important basic products for numerous syntheses. So, to stateonly one example, one may arrive at B-amino alcohols in that theketo-group is transformed into a tertiary alcohol group by reaction witha magnesium-organic compound and subsequently the aziridine ring isopened.

As will be seen from the above it has been made possible by the processof the invention to produce in a simple manner numerous already known aswell as new derivatives of pyrrole, pyrroline, pyrrolidine andaziridine.

We claim 1. A process for the production of pyrrole derivatives,comprising the following steps:

a. reacting a halogen compound of a single-unsaturated hydrocarbon ofthe formula wherein R R, and R may be the same or different and areselected from the group consisting of hydrogen, lower alkyl andhalogenated lower alkyl, with an acid chloride of the formula wherein Ris a member selected from the group consisting of lower alkyl, benzyland pyridyl, in the presence of a Lewis acid, thereby obtaining a B, 7-dichloroketone of the formula b. heating said dichloroketone at atemperature exceeding C. for more than 1 hour with an amine of theformula wherein R, is a member selected from the group consisting ofhydrogen, lower alkyl and benzyl thereby forming the correspondingheterocyclic nitrogen compound by splitting off hydrogen chloride.

2. The process in accordance with claim I, in which said Lewis acid isaluminum trichloride.

3. The process in accordance with claim 1, in which said singleunsaturated hydrocarbon is a member selected from the group consistingof allyl chloride, methallyl chloride and l,4-dichloro-2-butene.

4. The process in accordance with claim 1, in which said acid chlorideis a member selected from the group consisting of acetyl chloride,propionyl chloride, butyryl chloride, isobutyryl chloride, benzoylchloride and nicotinic acid chloride.

5. The process in accordance with claim 1, wherein the step a is carriedout in a solvent which is inert under the conditions of reaction.

6. The process in accordance with claim 1, wherein the step a is carriedout at temperatures below -l0 C.

'7. The process in accordance with claim 1, wherein said amine isammonia and is reacted with the B, ydichloroketone in the vapor phaseunder elevated pressure.

said amine has a boiling point above C and is reacted with the [3,y-dichloroketonc under normal pressure.

1 l. The process in accordance with claim 1, wherein obtained pyrrolederivatives are hydrogenated.

I i II II

2. The process in accordance with claim 1, in which said Lewis acid isaluminuM trichloride.
 3. The process in accordance with claim 1, inwhich said single unsaturated hydrocarbon is a member selected from thegroup consisting of allyl chloride, methallyl chloride and1,4-dichloro-2-butene.
 4. The process in accordance with claim 1, inwhich said acid chloride is a member selected from the group consistingof acetyl chloride, propionyl chloride, butyryl chloride, isobutyrylchloride, benzoyl chloride and nicotinic acid chloride.
 5. The processin accordance with claim 1, wherein the step a is carried out in asolvent which is inert under the conditions of reaction.
 6. The processin accordance with claim 1, wherein the step a is carried out attemperatures below -10 * C.
 7. The process in accordance with claim 1,wherein said amine is ammonia and is reacted with the Beta , gamma-dichloroketone in the vapor phase under elevated pressure.
 8. Theprocess in accordance with claim 1, wherein said amine is aliphaticamine and is reacted with the Beta , gamma -dichloroketone in the vaporphase.
 9. The process in accordance with claim 1, wherein the amine isdissolved in a solvent and at least partially is added to thedichloroketone as solution.
 10. The process in accordance with claim 1,wherein said amine has a boiling point above 100 * C and is reacted withthe Beta , gamma -dichloroketone under normal pressure.
 11. The processin accordance with claim 1, wherein obtained pyrrole derivatives arehydrogenated.